EP1499294B1 - Systeme de transport pour des micronutrients comprenant des lipides polymerises modifies avec des peptides - Google Patents
Systeme de transport pour des micronutrients comprenant des lipides polymerises modifies avec des peptides Download PDFInfo
- Publication number
- EP1499294B1 EP1499294B1 EP03727314A EP03727314A EP1499294B1 EP 1499294 B1 EP1499294 B1 EP 1499294B1 EP 03727314 A EP03727314 A EP 03727314A EP 03727314 A EP03727314 A EP 03727314A EP 1499294 B1 EP1499294 B1 EP 1499294B1
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- European Patent Office
- Prior art keywords
- leu
- transport system
- ile
- seq
- vitamin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Definitions
- the invention relates to a transport system for active substances comprising hybrid particles of at least one layer of lipid molecules and at least one ligand connected via a spacer unit, which is a peptide, characterized in that at least one polymerizable group is incorporated in the hybrid particles.
- the invention relates to a method for the transport of active ingredients.
- the invention also relates to a transport system for use as a medicament.
- the invention also relates to the use of the transport system for the preparation of a medicament for the treatment of nutritional deficiencies.
- micronutrients e.g. chronic or acute inflammatory processes, infections, ischemia, etc.
- diseases e.g. chronic or acute inflammatory processes, infections, ischemia, etc.
- the supply of micronutrients is an important prerequisite for normal cellular functions and thus for the maintenance or regeneration of cell aggregates.
- micronutrients also belongs to fat-soluble vitamins for the smooth running of general physiological processes. Their metabolism is subject to a very efficient control and often also a homeostatic regulation. This physiological balance collides in some way with indications where it would be advisable from a medical, especially nutritional, viewpoint to apply locally high micronutrient concentrations.
- systemic balance can only be circumvented by the administration of very high micronutrient concentrations.
- very high micronutrient concentrations there may be some heavy burdens on the entire organism, in particular the liver but also the kidneys, due to the high micronutrient concentration.
- a transport possibility is hydrophilic polymer gels of natural and synthetic origin (so-called hydrogels, eg alginate, fibrin, poly-lactate-glycolic acid copolymer (GLGLA) etc.).
- hydrogels eg alginate, fibrin, poly-lactate-glycolic acid copolymer (GLGLA) etc.
- the transport of hydrophobic drugs using these polymeric materials is not easy because polymeric hydrogels are generally water-swellable, and loading with, for example, hydrophobic micronutrients (such as fat-soluble vitamins or vitamin precursors) without further modifications of the hydrogel is not possible.
- Liposomes bearing short water-swellable polymer chains such as polyethylene glycol (PEG) at the surface also have increased long-term stability. This can be explained by the entropy elasticity of the polymers used on the surface of the liposomes.
- the first molecules that first come into contact with the particles used in a therapeutic treatment are proteins. As a result of adsorption of these proteins, a signal cascade is triggered, which ultimately causes the "disposal" of the supposed foreign body by the immune system.
- the adsorption of proteins on the surface of liposomes bearing short polymer chains causes these polymers to collapse. By restricting conformational freedom in this situation, the polymer consumes a great deal of energy in the form of entropy.
- the polymer escapes from this energetically unfavorable state by stretching again, which leads to a repulsion of the protein, analogously to a spring which is compressed and relaxes again.
- this process prevents adsorption of proteins and ultimately an immune system response.
- Parameters that influence this repulsive process are the surface concentration and the length (molecular mass) of the polymers as well as the phase behavior in mixtures with other molecular components of the liposomes.
- Liposomal systems incorporating PEG-modified lipids show half-lives of up to 45 hours in human studies.
- Many drug administrations employing liposomes and polymer-functionalized liposomes rely on passive delivery of the drugs to certain tissues. This means that a therapeutic improvement ultimately based on the long residence time of the particles in the body.
- these approaches however, one can not rule out that the active ingredients ultimately accumulate simultaneously in various tissues, even in those where the active ingredient is not needed or in the worst case also causes unwanted side effects.
- Liposomal structures are a suitable carrier system for drugs and allow the transport and release of such substances.
- Straight transport systems which are produced on the basis of liposomal structures, have gained in recent years greatly in therapeutic importance and are already widely used commercially.
- the residence time (half lives) of these formulations increases significantly, which is of tremendous therapeutic benefit.
- this can also be achieved by a corresponding adjustment and control of the physicochemical surface properties (such as charge) of the particulate systems.
- the drug daunorubicin citrate is packaged in passive, ie, "non-functionalized,” liposomes and used to treat Kaposi's sarcoma lesions.
- passive, ie, "non-functionalized,” liposomes and used to treat Kaposi's sarcoma lesions.
- the object of the invention is to specify a possibility for the stable target-oriented transport of active substances in a biological system.
- the object of the invention is achieved by the transport system according to the features in the characterizing part of claim 1.
- the advantage of the transport system is that by combining the lipid molecule with a peptide, the system not only lingers for a correspondingly long time in the body, but rather can actively communicate with cells.
- transport systems which have a defined composition and interaction of molecular building blocks as well as controllable structures in the submicrometer range, can additionally take up micronutrients in certain compartments and transport them to specific tissue types in a targeted manner.
- Such particulate transport systems which can actively communicate with biological tissue in addition to a structural / functional definition, are one of the great opportunities of modern biotechnology.
- Another advantage is that the active ingredients can be accumulated at the site of action to achieve a high concentration at the site of action and not a systemic burden on the entire organism is caused.
- the advantage here is that by introducing a spacer unit between the polar head group of the lipid molecule and the peptide steric hindrances and / or charge interference in the interaction of the hybrid particle with the binding partner, in particular a target cell, can be prevented.
- the particulate system can bind to both larger and non-adjacent binding partner by the spaced arrangement of the oligopeptides, because there are no obstructions due to lack of space expansion possibilities.
- the active ingredients can be targeted to the site of action and thereby do not burden the entire organism. As a result, it can also be avoided that, as in the worst case, it is to be feared that undesired side effects of the active substances occur on all cells.
- the development of the transport system according to claim 8 proves to be advantageous because thereby the transport of the active ingredients directly to the target cells, in particular to skin cells, preferably to fibroblasts, can take place and it comes thereby to no load on other cells and thus other organs.
- the hybrid particles do not have to be arranged along a carrier but form automatically to 3-dimensional structures. It also proves advantageous that by arranging the hybrid particles active ingredients can be packaged and thus protected against metabolic processes on the way to the site of action. Another advantage is that by packaging the active ingredients in a particulate transport system immunological attacks and degradation processes can be avoided and thus arrive the active ingredients in their original form at the site of action.
- the release of the micronutrients can be controlled by the crosslinking of the hybrid particles by polymerizable groups.
- the precise control of physico-chemical surface properties, particularly the concentration and presentation of a peptide at the interface, is another important criterion for the successful use of active particulate drug delivery systems .
- micronutrients can support the prevention of diseases and the regeneration of the organism.
- the orthomolecular properties of micronutrients set biochemical stimuli that can be meaningfully utilized and answered by the organism because the body is dealing with "original parts", ie, with substances that are familiar to it.
- original parts ie, with substances that are familiar to it.
- the transport system enables the targeted transport and release of the provided amounts of vitamins, which the organism needs for vital functions, but which can not or not sufficiently be synthesized in the metabolism and therefore have to be supplied regularly with food .
- vitamins are also components of coenzymes that catalyze cell metabolism.
- Advantageous according to claim 14 proves that minerals and trace elements, which are essential for warm-blooded animals, can be supplied by a particulate transport system.
- the elements sodium, potassium, magnesium and calcium are responsible for the maintenance of homeostasis in physiological concentrations.
- the introduction of synthetic diets in the treatment of metabolic abnormalities based on congenital genetic defects, the development of intravenous nutrition and the dialysis treatment of ESRD patients reveal the iatrogenic risks, the importance of alimentary intake, and if this is not possible emphasize the importance of supplementing these elements.
- Trace elements present in the body in minimal concentrations (less than 0.005% of body weight) play an important role in human physiology. However, with the increasing development of synthetic foods, excessive incorporation of these elements may occur.
- alimentary intake leads to systemic stress on the whole organism causing toxicity phenomena, which often can manifest itself only after years, and therefore the need for targeted delivery of these elements becomes all the more evident.
- taurine is involved in a number of physiological processes, e.g. bile acid conjugation, osmoregulation, detoxification of xenobiotics, stabilization of cell membranes, control of cellular calcium flow and modulation of neuronal excitability.
- Lower taurine levels are associated with retinal degeneration, retarded growth and cardiomyopathy.
- arginine increases lymphocyte count and generally promotes the formation of immunocompetent cells. In addition, it increases the cytolytic capacity of macrophages and NK cells. It also plays an important role in wound healing. Histidine acts as an antiallergic and serves as a precursor of histamine. Isoleucine, leucine and valine are important components of muscle proteins. Lysine is the main constituent of collagen, carnitine antibodies, hormones and enzymes, supports wound healing and promotes herpes simplex healing.
- Methionine is an antioxidant that detoxifies the liver and is essential for the selenium action (absorption, transport, bioavailability). Phenylalanine has an antidepressant effect and prolongs the effect and increases the activity of endorphins. Threonine is a lipotropic factor. Tryptophan is important for the synthesis of vitamin B3 and is a precursor of serotonin and melatonin (sleep rhythm).
- optimal supply of essential fatty acids is of paramount importance to the organism. So they get e.g. the elasticity of the membranes of all body cells as well as the mitochondria and ensure cell rejuvenation. They occur in the gonads and form the building blocks for the body's own hormone production in the endocrine gland system as well as in the cell tissue.
- a prominent role among the essential fatty acids play linoleic and ⁇ -linolenic acid. They serve as structural elements of the cell membrane and control with the products resulting from them, e.g. Prostaglandins, thromboxane and leukotrienes, many vital processes in the organism.
- Arachidonic acid occurs only in animal fats and is a starting material for prostaglandin synthesis. Targeted delivery of arachidonic acid to prostaglandin formation sites via the cyclooxygenase-1 metabolic pathway avoids systemic excess supply of arachidonic acid with a negative influence on rheumatic joint inflammation.
- the object of the invention is achieved independently by a method according to the features in the characterizing part of claim 18.
- the advantage of this is that a systemic burden on the organism can be avoided because the active substance is released only in the target cell. As a result, systemic side effects due to excessive concentrations of the drugs in cells other than the target cells can be avoided.
- the object of the invention is also independent by the use of the transport system solved according to claim 19.
- the advantage here is that a preventive and regenerative influence on the organism can be achieved.
- the transport system can be brought by the topical application directly to the site of action and the transport of the drug through the cell membrane and not only via the blood or lymphatic system.
- micronutrients such as provitamins, vitamins, minerals and trace elements, amino acids, fatty acids, polyphenols, hormones and organ extracts or their synthesis products, such as, for example, Pancreatin, bile acid, cartilage ground substance, etc., but of course also dyes, e.g. Contrast agents that need to be transported targeted for imaging in medical examinations, understood.
- Hybrid particles 2 of lipid molecules 3, which are modified with certain peptides 5 on the polar head group 7, can be formed by the symmetrical arrangement of the nonpolar hydrocarbon chains 8 for the construction of self-organized three-dimensional structures, in particular transport systems 1, such as liposomes, micelles and oil-in-water Emulsions are used. It is an exact control of important physico-chemical Surface properties, such as the surface concentration of the peptide 5, possible.
- the oligopeptide sequence is a control sequence for the targeted addressing of the hybrid particle 2 and / or the transport system 1.
- bioactive peptide sequences which are bound in a controlled manner on the surface of these systems, provide the basis for efficient and specific delivery of the particles to specific cells in certain tissues as well a prevention of nonspecific interactions with proteins.
- bioactive oligopeptides 6 ligands are adapted, which are typically found in extracellular space signaling proteins.
- hybrid particle transport systems 1 with oligopeptides 6 with at least one of the sequences Gly-Arg-Gly-Asp-Ser-Pro (SEQ ID NO: 1), which forms a fibronectin receptor binding site, allows Tyr-Ile-Glu-Ser Arg (SEQ ID NO: 2), which is a laminin receptor binding site, and / or Ala-Asp-Gly-Glu-Ala (SEQ ID NO: 3), which is a collagen receptor binding site, targeted delivery of drugs 10 to cells of the skin, in particular to fibroblasts.
- hybrid particles 2 with oligopeptides 6 having at least one of the sequences Val-Arg-Leu-Leu-Asn-Asn (SEQ ID NO: 4), Val-Arg are suitable Leu-Asn-Asn-Trp-Asp (SEQ ID NO: 5), Gly-Arg-Val-Arg-Leu-Leu-Asn-Asn (SEQ ID NO: 6), binding sites for the retinol binding protein on RP65 characterize.
- hybrid particles 2 are suitable with oligopeptides 6 having at least one of the sequences Met-Thr-Ala-Gly-Ala-Gly (SEQ ID NO: 7), Leu-Ser-Gly-Ala-Leu-Arg (SEQ ID NO: 8 ), Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Leu-Thr-Met-Val-Leu-Leu-Phe-Val-Met-Trp-Met (SEQ ID NO: 9), wherein any portion of the amino acid sequence of SEQ ID NO: 9 can be selected as the binding site, such as Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Leu (SEQ ID NO: 10), Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Thr-Met-Val-Leu-Leu-Leu
- oligopeptides 6 are by definition all outside and by choosing the concentrations of lipid molecules 3 and ligand-modified lipid molecules 3, different emulsion phases can be controllably adjusted in terms of hydrodynamic dimensions and physical-chemical surface properties become.
- a spacer unit 4 For the spacer arrangement of the oligopeptide 6 on the lipid molecule 3, different substances can be used as a spacer unit 4, e.g. a sequence of amino acids or chemically inert substances, such as.
- nanoparticles such as carbon nanotubes, nanofilaments, colloids, etc., are used.
- the controlled release of micronutrients from the particles is achieved by the incorporation of polymerizable groups in the molecular structure of the hybrid particles 2 used and thus by the cross-linking of the lipid layers in two dimensions.
- Parameters e.g. the size and shape (hydrodynamic dimensions) of the hybrid particles 2, physico-chemical surface properties and the stability of the transport system 1 are each of great importance for the targeted delivery of micronutrients.
- the polymerization within the self-assembled layers results in stabilization and can be used to control the release of micronutrients introduced. Controlling the release of micronutrients aims at not only enriching certain micronutrients in the target tissue, but also at a high concentration over a longer period of time.
- lipid molecules 3 which freely diffuse laterally within the mono- or double layers, thus allowing a lively exchange of molecules inside and outside the particles.
- This can be done, for example the incorporation of polymerizable groups in the hybrid particles 2 and subsequent polymerization or partial polymerization in two dimensions (within the lipid layers) take place.
- diacetylene lipids can be used which polymerize by allowing the formation of self-assembled structures such as long-term stable vesicles, stable tubes with very high persistence, helical microstructures, etc.
- This polymerization reaction is photochemically controllable and the diacetylene lipids polymerize almost exclusively within a crystalline lipid phase.
- the result is a polymer that has an extended, conjugated electron system and as a result, absorbs light in the visual range.
- the location of the absorption is dependent on the structure (conformation) of the polymer and can be influenced and shifted by various parameters, such as a temperature increase and / or mechanical stress, such as the binding of a ligand to a corresponding receptor.
- Partially polymerized transport systems 1 may also be prepared by the addition of non-polymerizable hybrid particles 2 which are stable in various physiological environments (pH, ionic strength, etc.). For steric shielding (suppression of non-specific interactions, eg with proteins) lipopolymers are incorporated. To better analyze these structures, fluorescent lipids can also be incorporated. In particular, the length and concentration of the lipopolymers used affects the bioactivity of the transport system 1.
- Polymerizable hybrid particles 2 can also be used for the preparation of thermodynamically stable microemulsions so as small as possible bioactive transport systems 1 with a diameter with a lower limit of 5 nm, in particular 10 nm, preferably 15 nm and an upper limit of 180 nm, preferably 160 nm, in particular 140 nm.
- an area with a lower limit of 20 nm, in particular 30 nm and an upper limit of 120 nm, in particular 100 nm has been found.
- These thermodynamically stable microemulsions have the largest possible hydrophobic transport volume.
- these emulsions may also contain polymerizable lipids and lipopolymers as well as further hydrophobic components.
- the phase behavior of this oil-in-water emulsion is a function of the concentration of the individual parameters of the temperature and the ionic strength of the medium with the aim to produce a thermodynamically stable emulsion phase.
- hybrid particles 2 can also be synthesized and characterized on the basis of natural phospholipids.
- the phospholipid is bound directly to the orthogonally protected peptide 5 and, in a final step, the molecule and all protective groups are split off from the solid phase. The purification is carried out by means of high performance chromatography (HPLC).
- the modified phospholipids produced are used together with unmodified lipids for the construction of bioactive transport systems 1 and emulsions.
- FTIR Fourier transform infrared spectroscopy
- NMR nuclear magnetic resonance spectroscopy
- MS mass spectroscopy
- Bioactive planar surfaces which are prepared via the self-assembly of these synthetic hybrid particles 2 and subsequent modification of solid substrates, show a high potential for adhesion.
- planar surfaces are also modified with polymerized monolayers of the hybrid particles 2. Cells can adhere to these surfaces and spread. Furthermore, these surfaces can be reoccupied with cells as often as they are no longer detachable from the surface by the polymerization and thus cells can be removed relatively easily several times. It is also possible to quantify the results.
- Drug delivery systems 1 can be used to treat conditions resulting from inadequate micronutrient delivery.
- the transport system 1 can also transport active ingredients 10 for cosmetic applications and can be applied both orally and topically.
- Hybrid particles 2 with oligopeptide sequences can be used as a transport system 1 for tocopherols for skin cells, in particular fibroblasts.
- the targeted delivery of micronutrients both preventive and regenerative processes, such as. supports the tissue preservation and wound healing of the skin. Burns and wound healing lead to a decrease in the concentration of antioxidants. This is especially true for tocopherols, which are quantitatively the most important fat-soluble vitamins of the skin. Especially with burns, however, the systemic supply of micronutrients is particularly bad or no longer available.
- tocopherols can be directly enriched in the target cells and released in a controlled manner.
- the active ingredients 10 can be held, accumulated and released due to the specific ligands in different skin layers and thereby act locally.
- the penetration behavior is also positively influenced by the small particle size.
- Three-dimensional skin models can be used as a model for the examination.
- a transport system 1 comprising hybrid particles 2 with the oligopeptide sequence Val-Arg-Leu-Leu-Asn-Asn (SEQ ID NO: 4) is used.
- the targeted delivery of micronutrients supports preventive processes such as the prevention of age-related macular degeneration (AMD).
- AMD age-related macular degeneration
- AMD has been shown to have low concentrations of the carotenoids lutein and zeaxanthin in the retina.
- the provitamins are targeted to the target cells.
- Cell lines of the retinal epithelium can be used as a model system for the eye.
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Claims (22)
- Système de transport pour des principes actifs comprenant des particules hybrides en au moins une couche de molécules de lipide et au moins un ligand lié par une unité entretoise, ligand qui est un peptide, caractérisé en ce qu'au moins un groupe polymérisable est incorporé dans la particule hybride.
- Système de transport selon la revendication 1, caractérisé en ce que l'unité entretoise est formée par des acides aminés, une substance chimiquement inerte comme une nanoparticule, choisie parmi un groupe comprenant des nanotubes de carbone, des nanofilaments ou des colloïdes.
- Système de transport selon la revendication 1 ou 2, caractérisé en ce que les molécules de lipide sont des lipides polymérisables et/ou des lipides « naturels » comme par exemple des stéroïdes, des glycolipides, des phospholipides, des sphingolipides, des polyisoprénoïdes.
- Système de transport selon l'une quelconque des revendications précédentes, caractérisé en ce que le peptide est un oligopeptide.
- Système de transport selon la revendication 4, caractérisé en ce que l'oligopeptide présente une longueur, choisie dans un intervalle avec une limite inférieure de 4 acides aminés, de préférence de 5 acides aminés, en particulier de 6 acides aminés et une limite supérieure de 18 acides aminés, de préférence de 20 acides aminés, en particulier de 22 acides aminés.
- Système de transport selon la revendication 4 ou 5, caractérisé en ce que la séquence d'oligopeptides est complémentaire à la séquence d'un récepteur sur une cellule.
- Système de transport selon l'une quelconque des revendications 4 à 6, caractérisé en ce que l'oligopeptide présente une séquence choisie parmi un groupe comprenant les séquences Gly-Arg-Gly-Asp-Ser-Pro (SEQ ID NO: 1), Tyr-Ile-Glu-Ser-Arg (SEQ ID NO: 2), et/ou Ala-Asp-Gly-Glu-Ala (SEQ ID NO: 3).
- Système de transport selon l'une quelconque des revendications 4 à 6, caractérisé en ce que l'oligopeptide présente une séquence choisie parmi un groupe comprenant les séquences Val-Arg-Leu-Leu-Asn-Asn (SEQ ID NO: 4), Val-Arg-Leu Leu-Asn-Asn-Trp-Asp (SEQ ID NO: 5), Gly-Arg-Val-Arg-Leu-Leu-Asn-Asn (SEQ ID NO: 6), Met-Thr-Ala-Gly-Ala-Gly (SEQ ID NO: 7), Leu-Ser-Gly-Ala-Leu-Arg (SEQ ID NO: 8). Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Leu-Thr-Met-Val-Leu-Leu-Phe-Val-Met -Trp-Met (SEQ ID NO: 9), Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Leu (SEQ ID NO: 10), Ile-Val-Ala-Ile-Leu-Ile-Cys-Ile-Leu-Ile-Leu-Leu-Thr-Met-Val-Leu-Leu-Phe (SEQ ID NO: 11), Ile-Val-Ala-Ile-Leu-Ile (SEQ ID NO: 12), Cys-Ile-Leu-Ile-Leu-Leu (SEQ ID NO: 13), Thr-Met-Val-Leu-Leu-Phe (SEQ ID NO: 14) et/ou Leu-Phe-Val-Met-Trp-Met (SEQ ID NO: 15).
- Système de transport selon l'une quelconque des revendications précédentes, caractérisé en ce que les particules hybrides forment des structures tridimensionnelles comme par exemple des vésicules, des microsphères, des nanoparticules, des tubes.
- Système de transport selon l'une quelconque des revendications précédentes, caractérisé en ce que le principe actif est au moins un micronutriment.
- Système de transport selon la revendication 10, caractérisé en ce que ledit au moins un micronutriment est au moins une substance choisie parmi le groupe comprenant des provitamines, des vitamines, des substances minérales et des oligoéléments, des acides aminés, des acides gras, des polyphénols, des hormones et des extraits d'organes, respectivement leurs produits de synthèse, comme par exemple la pancréatine, l'acide biliaire, la substance de base du cartilage.
- Système de transport selon la revendication 10 ou 11, caractérisé en ce que la vitamine est choisie parmi le groupe comprenant des composés naturels et synthétiques à structure de rétinoïde (vitamine A), le complexe des vitamines B, l'acide ascorbique (vitamine C), les calciférols (vitamine D), les tocophérols (vitamine E), la vitamine K, les flavonoïdes et la biotine.
- Système de transport selon l'une quelconque des revendications 10 à 12, caractérisé en ce que ladite au moins une vitamine est choisie parmi le groupe comprenant le rétinol, l'acétate de rétinyle, le palmitate de rétinyle, le 3,4-didéhydrorétinol (vitamine A2), le rétinal, l'acide rétinique et des provitamines, comme par exemple l'α-, le β-, le γ-carotène, la lutéine, la zéaxanthine, la thiamine (vitamine B1) respectivement le chlorhydrate de thiamine respectivement le mononitrate de thiamine, la riboflavine (vitamine B2) respectivement le sodium-riboflavine-5-phosphate, la niacine (vitamine B3) respectivement l'acide nicotinique respectivement le neacin, l'acide pantothénique (vitamine B5) respectivement le calcium-D-pantothénate respectivement le sodium-D-pantothénate respectivement le D-panthénol, la pyridoxine (vitamine B6) respectivement le chlorhydrate de pyridoxine respectivement le pyridoxine-5-phosphate respectivement le dipalmitate de pyridoxine respectivement le phosphate de pyridoxal, l'acide folique (vitamine B9) respectivement l'acide ptéroylglutamique, la cobalamine (vitamine B12) respectivement la cyanocobalamine respectivement l'hydroxycobalamine, la biotine, la choline, l'inosite et l'acide p-aminobenzoïque, l'acide L-ascorbique, le L-ascorbate de sodium, le L-ascorbate de calcium, le L-ascorbate de potassium et le L-ascorbyl-6-palmitate, l'ergocalciférol (vitamine D2), le cholécalciférol (vitamine D3), le 1,25-dihydroxycholécalciférol et les provitamines ergostérol respectivement 7-déhydrocholestérol, le D-α-tocophérol, le DL-α-tocophérol, l'acétate de D-α-tocophéryle, l'acétate de DL-α-tocophéryle et le succinate de D-α-tocophéryle, la phylloquinone (vitamine K1), la ménoquinone (vitamine K2), la ménadione (vitamine K3) et la ménadionehydroxyquinone (vitamine K4).
- Système de transport selon la revendication 10 ou 11, caractérisé en ce que ladite au moins une substance minérale, respectivement ledit au moins un oligo-élément, dans l'ordre de leur signification pour l'organisme, sont choisis parmi un groupe comprenant Na, K, Mg, Ca, Fe, I, Cu, Mn, Zn, Co, Mo, Se, Cr, F, Si, Ni, As, Sn, V, P, Cl, B, Al et Br.
- Système de transport selon la revendication 10 ou 11, caractérisé en ce que ledit au moins un composant est choisi parmi un groupe comprenant le coenzyme Q-10, la quercétine, la broméline, l'inositol, la choline, le pycnogénol, la carnitine, la taurine, le méso-inositol.
- Système de transport selon la revendication 10 ou 11, caractérisé en ce que ledit au moins un acide aminé essentiel est choisi parmi le groupe comprenant l'histidine, l'isoleucine, la leucine, la lysine, la méthionine, la phénylalanine, la thréonine, le tryptophane, la valine et l'arginine.
- Système de transport selon la revendication 10 ou 11, caractérisé en ce que ledit au moins un acide gras est choisi parmi le groupe comprenant l'acide linoléique, l'acide linolénique, l'acide arachidonique.
- Procédé pour le transport de principes actifs, caractérisé en ce que l'on utilise le système de transport selon l'une quelconque des revendications 1 à 17.
- Système de transport selon l'une quelconque des revendications 1 à 17 pour une utilisation comme médicament.
- Utilisation du système de transport selon la revendication 19 à la préparation d'un médicament pour le traitement de carences alimentaires.
- Utilisation du système de transport selon la revendication 20 pour une administration topique et orale.
- Utilisation du système de transport selon l'une quelconque des revendications 1 à 17, caractérisé en ce qu'il est utilisé dans les industries pharmaceutiques, cosmétiques et alimentaires.
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AT6562002 | 2002-04-29 | ||
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PCT/EP2003/003973 WO2003092647A2 (fr) | 2002-04-29 | 2003-04-16 | Systeme de transport dans des systemes biologiques |
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GB2463801B (en) * | 2007-03-20 | 2011-07-13 | Univ Plymouth | Isoprenoid compounds, their isolation and use |
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PL296382A1 (en) * | 1991-02-02 | 1993-11-02 | Nika Health Products Ltd Li Li | Artificial membrane beads containing functionally active peptides responsible for fusion as a drug administering system |
JP2579730B2 (ja) * | 1993-01-22 | 1997-02-12 | 株式会社ディ・ディ・エス研究所 | ペプチド−脂質誘導体及びリポソーム |
CA2126648C (fr) * | 1993-11-09 | 2000-10-10 | Tomas De Paoli | Liposomes renfermant du fer (ii) biodisponible; methode de preparation |
DE69528355T2 (de) * | 1994-02-04 | 2003-05-15 | Lipocore Holding Ab Stockholm | Doppelschicht-zusammensetzungen aus digalactosyldiacylglycerol enthaltendem galactolipid |
CA2218541A1 (fr) * | 1995-06-07 | 1996-12-19 | Imarx Pharmaceutical Corp. | Nouvelles compositions ciblees, destinees a une utilisation diagnostique et therapeutique |
US6120751A (en) * | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
ATE322255T1 (de) * | 1997-12-23 | 2006-04-15 | Inex Pharmaceuticals Corp | Polyamid-oligomere |
US6187335B1 (en) * | 1997-12-31 | 2001-02-13 | Orasomal Technologies, Inc. | Polymerizable fatty acids, phospholipids and polymerized liposomes therefrom |
US6916488B1 (en) * | 1999-11-05 | 2005-07-12 | Biocure, Inc. | Amphiphilic polymeric vesicles |
EP1255568A2 (fr) * | 2000-02-18 | 2002-11-13 | Watson Pharmaceuticals, Inc. | Conjugues cibles sur des recepteurs cibles |
US6761901B1 (en) * | 2000-05-02 | 2004-07-13 | Enzrel Inc. | Liposome drug delivery |
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- 2003-04-16 DE DE50312971T patent/DE50312971D1/de not_active Expired - Lifetime
- 2003-04-16 AU AU2003233981A patent/AU2003233981A1/en not_active Abandoned
- 2003-04-16 PT PT03727314T patent/PT1499294E/pt unknown
- 2003-04-16 DK DK03727314.1T patent/DK1499294T3/da active
- 2003-04-16 ES ES03727314T patent/ES2351967T3/es not_active Expired - Lifetime
- 2003-04-16 EP EP03727314A patent/EP1499294B1/fr not_active Expired - Lifetime
- 2003-04-16 WO PCT/EP2003/003973 patent/WO2003092647A2/fr active Application Filing
- 2003-04-16 US US10/512,737 patent/US20090074847A1/en not_active Abandoned
- 2003-04-16 AT AT03727314T patent/ATE476963T1/de active
- 2003-04-16 JP JP2004500832A patent/JP2005529137A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
PT1499294E (pt) | 2010-12-07 |
JP2005529137A (ja) | 2005-09-29 |
US20090074847A1 (en) | 2009-03-19 |
AU2003233981A1 (en) | 2003-11-17 |
AU2003233981A8 (en) | 2003-11-17 |
ES2351967T3 (es) | 2011-02-14 |
WO2003092647A2 (fr) | 2003-11-13 |
WO2003092647A3 (fr) | 2004-01-08 |
EP1499294A2 (fr) | 2005-01-26 |
DK1499294T3 (da) | 2010-12-06 |
DE50312971D1 (de) | 2010-09-23 |
ATE476963T1 (de) | 2010-08-15 |
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